Adenosine acts as a modulator of numerous physiological functions through two classes of extracellular membrane-bound receptors. The A1- and A2-adenosine receptors, currently delineated in different tissues according to the rank order of potency of certain adenosine analogues, are in general linked to adenylate cyclase in either an inhibitor (A.sub.1) or a stimulatory (A.sub.2) manner.
In this invention, the following abbreviations are used: N.sup.6 -R-1-phenyl-2-propyladenosine is R-PIA; N.sup.6 -cyclohexyladenosine is CHA; N-ethyladenosine-5'-uronamide is NECA.
At A.sub.1 -receptors the order of potency is R-PIA, CHA&gt;NECA&gt;S-PIA, while at A.sub.2 -receptors NECA is clearly the most potent. The A.sub.2 -adenosine receptor is associated with vasodilation producing a lowering of blood pressure, inhibition of platelet aggregation, and the antidiuretic effect of adenosine, and other physiological effects.
Adenosine analogues substituted at N.sup.6 with spacer arms designed for attachment to soluble macromolecules or to solid supports for affinity chromatography are agonists at the A.sub.2 -adenosine receptor that mediates coronary vasodilation in the dog. The most active analogues have spacer arms terminating in --NH.sub.2, --NHCH.sub.3 or in a biotin residue. Comparisons of coronary vasoactivity with affinity for brain A.sub.1 adenosine receptors identified one biotin-containing analogue as relatively selective for coronary A.sub.2 receptors. The complex of this analogue with avidin retains coronary vasoactivity.
There has been noted a "functionalized congener" approach to the design of adenosine receptor ligands, utilizing a regioselectively incorporated spacer chain. The potency of binding at the A.sub.1 -receptor in rat cerebral cortical membranes is modulated by the presence of various attached groups or "carriers" linked to the chain through a stable covalent bond. This set of functionalized congeners is designed through a strategy of stepwise chain elongation in which intermediate structures were screened for potency to select structural elements which promote receptor binding. The purpose of this congener approach includes the identification of new animal therapeutic agents.